Atrial natriuretic peptides (ANP) are circulating hormones which are synthesized in the atrium of the heart and secreted. The hormones regulate blood pressure through their natriuretic, diuretic and vasorelaxant activities, as well as inhibition of aldosterone secretion from the adrenal gland, inhibition of renin secretion from the kidney, and functional antagonism of the renin-angiotensin system. The ANP hormones have been widely studied, and a large number of analogs have been proposed. Copending U.S. application Ser. Nos. 138,893, filed Dec. 24, 1987 and 237,299, filed Aug. 26, 1988, assigned to the same assignee and incorporated herein by reference disclose a series of linear analogs of the native ANP, which native ANPs are cyclic disulfides. Cyclic analogs are disclosed in copending application Ser. No. 174,739, filed May 31, 1988, assigned to the same assignee and also incorporated herein by reference. These copending applications are the latest filed in a series which includes U.S. Ser. No. 168,661, filed Mar. 16, 1988 (allowed), U.S. Ser. No. 921,360 (abandoned), U.S. Ser. No. 904,091 (abandoned), U.S. Ser. No. 868,312 now issued as U.S. Pat. No. 4,757,048, and U.S. Ser. No. 795,220 (abandoned). Various analogs have also been proposed by others, and the literature relating to ANP analogs is now quite extensive.
It is known that the half life of ANPs in the blood stream is relatively short and that many of the analogs of ANP, such as those set forth in the above-referenced U.S. Ser. No. 138,893, appear to act by blocking the clearance receptors for ANP, thus increasing the opportunity for the natively produced ANPs to exert their effects. Two distinct pathways have now been identified which appear to contribute to most ANP clearance. The first pathway relates to receptor mediated metabolic clearance which has sufficient affinity and capacity to account for 70-80% of total ANP clearance from the system (Maack, T., et al, Science (1987) 238:675-679, EPO Publication No. 223,143). It was further determined that an additional, nonsaturatable clearance pathway also operates if the specific receptor pathway is inhibited, Almeida, F. A., Amer J Physiol (1988) (submitted).
On the basis of additional evidence from a variety of sources, it is believed that the nonsaturatable clearance pathway may involve the activity of a peptidase, neutral endopeptidase 24.11 (EC3.4.24.11), commonly referred to as endopeptidase 24.11. U.S. Pat. No. 4,740,499, issued Apr. 26, 1988, describes and claims a method of prolonging or enhancing the bioactivity of an atrial peptide using two specific inhibitors of endopeptidase 24.11, thiorphan or kelatorphan. These inhibitors are administered simultaneously with the atrial peptide. EPO Application Publication No. 254,032, published Jan. 27, 1988, also describes and claims the use of inhibitors of endopeptidase 24.11, or of neutral metallopeptidases in general, to treat hypertension, either alone or in association with ANP (or with an angiotensin converting enzyme inhibitor). In this disclosure, the inhibitors of the neutral metalloendopeptidase include thiorphan but further include compounds disclosed in U.S. Pat. No. 4,610,816, i.e., a substantial class of compounds, and compounds disclosed in EPO Application Publication No. 117,429 which also includes a substantial class. Reference is also made to compounds disclosed in U.S. Ser. No. 32,153, filed Mar. 27, 1987, U.S. Pat. No. 4,513,009 and European Application 38,046. In addition, a large volume of literature supports the conclusion that endopeptidase 24.11 is responsible for the extracellular inactivation of ANP (Stevenson, S. L., et al, Biochem J (1987) 243:183-187; Olins, G. M., et al, Biochim Biophys Acta (1987) 901:97-100; Koehn, J. A., et al, J Biol Chem (1987) 262:11623-11627); including the observation that a metabolic fragment of ANP isolated from human plasma is identical to the primary cleavage product of ANP treated with endopeptidase 24.11 (Yandle, T., et al, Biochem Biophys Res Commun (1987) 146:832-839).
It has also been observed by others that inhibitors of endopeptidase 24.11 potentiate the biological responses of administered ANP (Fennell, S. A., et al, FASEB J (1988) 2:A936; Seymour, A. A., et al, ibid; Trapani, A. J., et al, ibid; McMartin, C., et al, ibid; Zimmerman, M. B., et al, ibid:A937).
In addition to the use of thiorphan, there has been disclosed a variety of strategies for the inhibition of endopeptidase 24.11. These strategies include the use of a metal binding substituent appropriately spaced from an aromatic moiety. Roques, B. P., et al, Nature (1980) 288:286-288; Gordon, E. M., et al, Life Sci (1983) 33(Supplement 1):113-116; Mumford, R. M., et al, Biochem Biophys Res Comm (1982) 109:1303-1309; Fournie-Zaluski, M. C., et al, J Med Chem (1983) 26:60-65; Waksman, G., et al, Biochem Biophys Res Comm (1985) 131:262-268.
Blockage of both the specific receptor and the nonsaturatable endopeptidase 24.11 based clearance mechanisms by suitable inhibitors should greatly enhance the circulating levels of ANP and prolong the activity of the endogenous hormones. Indeed, it has been shown that conscious rats treated with an ANP clearance receptor-specific ligand in combination with the endopeptidase 24.11 inhibitor thiorphan results in greater diuresis and natriuresis than blockade of either pathway alone (Koepke, J., et al, FASEB Jour (1988) 2:A527. However, administration of inhibitors of these pathways separately carries the disadvantage that cerebral endopeptidase 24.11 will also be inhibited since thiorphan is capable of crossing the blood-brain barrier (Bourgoin, S., et al, J Pharm Exp Ther (1986) 238:360-366). This disadvantage could be overcome by utilization of a single agent which would block the clearance receptors for ANP, as well as inhibiting the alternate nonsaturatable enzymatic pathway.
The compounds of the invention described herein incorporate endopeptidase 24.11 inhibition functionality (or functionality which inhibits cleavage at Cys105-Phe106 of ANP) into analogs which also bind the ANP clearance receptors. Surprisingly, the elements which result in cleavage inhibition do not interfere with the clearance receptor binding capability of these compounds.